Effects of different sodium–glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a network meta-analysis

Background This systematic review and meta-analysis aimed to explore the effects of different sodium–glucose cotransporter-2 inhibitors (SGLT2i) on prognosis and cardiac structural remodeling in patients with heart failure (HF). Methods Relevant studies published up to 20 March 2024 were retrieved from PubMed, EMBASE, Web of Science, and Cochrane Library CNKI, China Biomedical Literature Service, VIP, and WanFang databases. We included randomized controlled trials of different SGLT2i and pooled the prognosis data of patients with HF. We compared the efficacy of different SGLT2i in patients with HF and conducted a sub-analysis based on left ventricular ejection fraction (LVEF). Results We identified 77 randomized controlled trials involving 43,561 patients. The results showed that SGLT2i significantly enhanced outcomes in HF, including a composite of hospitalizations for HF and cardiovascular death, individual hospitalizations for HF, Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, left atrial volume index (LAVi), and LVEF among all HF patients (P < 0.05) compared to a placebo. Sotagliflozin was superior to empagliflozin [RR = 0.88, CI (0.79–0.97)] and dapagliflozin [RR = 0.86, CI (0.77–0.96)] in reducing hospitalizations for HF and CV death. Dapagliflozin significantly reduced hospitalizations [RR = 0.51, CI (0.33–0.80)], CV death [RR = 0.73, CI (0.54–0.97)], and all-cause mortality [RR = 0.69, CI (0.48–0.99)] in patients with HF with reduced ejection fraction (HFrEF). SGLT2i also plays a significant role in improving cardiac remodeling and quality of life (LVMi, LVEDV, KCQQ) (P < 0.05). Among patients with HF with preserved ejection fraction (HFpEF), SGLT2i significantly improved cardiac function in HFpEF patients (P < 0.05). In addition, canagliflozin [RR = 0.09, CI (0.01–0.86)] demonstrated greater safety compared to sotagliflozin in a composite of urinary and reproductive infections of HFpEF patients. Conclusion Our systematic review showed that SGLT2i generally enhances the prognosis of patients with HF. Sotagliflozin demonstrated superiority over empagliflozin and dapagliflozin in a composite of hospitalization for HF and CV death in the overall HF patients. Canagliflozin exhibited greater safety compared to sotagliflozin in a composite of urinary and reproductive infections of HFpEF. Overall, the efficacy of SGLT2i was greater in HFrEF patients than in HFpEF patients.


Introduction
Heart failure (HF) results from either contraction or relaxation dysfunction of the heart, leading to multisystem symptoms and signs.Despite a decrease in the agestandardized prevalence of HF from 1990 to 2019, the reduction is not significant, and HF remains a significant cause of disability and death worldwide (1).Currently, in developed countries (2)(3)(4), such as Britain, France, and the United States, the prevalence of HF ranges from 1.5% to 2.0%, while in developing countries (5) and regions, such as Asia and Africa, it spans from 1.3% to 6.7%.According to the latest definitions by the European and American Heart Association, HF is categorized into three main types, namely, HF with mildly reduced ejection fraction (HFrEF) (LVEF, <40%), HF with moderately reduced ejection fraction (LVEF, 40%-50%), and HF with preserved ejection fraction (HFpEF) (EF, ≥50%).However, many previous meta-analyses defined HFpEF as EF ≥ 45%, which contrasts with the current HF classification.Hence, our study adopts the definition of HFpEF ≥ 50%.
SGLT2i is a new class of antidiabetic medications originally developed for managing diabetes.

Data extraction
Literature screening involved two researchers who independently reviewed articles based on the established inclusion and exclusion criteria.After individual assessments, they cross-checked their selections to ensure consistency.Key information, such as the first author's name, study design, baseline characteristics, and study endpoints, was systematically extracted from each article.

Literature quality evaluation
The quality of the included studies was independently assessed by two researchers using the "risk of bias assessment criteria" from the Cochrane Reviewers' Handbook (version 5.1.0).The evaluation of the RCTs involved the following components: (1) randomized method, (2) allocation concealment, (3) blinding of participant personnel and outcome assessors, (4) completeness of outcome data, (5) absence of selective outcome reporting, and (6) clarity of reasons for losses to follow-up or discontinuation.

Statistical analysis
The statistical analysis was conducted using Stata 15.1 software for network meta-analysis.Relative risks or odds ratios were determined for dichotomous variables, while continuous variables were analyzed using the frequentist methodology in network meta-analysis.Heterogeneity was set as I 2 < 50% and p > 0.01 for the fixed effect model.Otherwise, the random effects model was applied.Pooled results for continuous variables were expressed as the mean difference (MD).The surface under the cumulative ranking (SUCRA) was employed to indicate the preferred ranking of each treatment.Small sample effects were investigated through a network funnel plot.P < 0.05 was considered statistically significant.

Basic characteristics and quality assessment
A total of 6,229 relevant literature sources were identified through a comprehensive search across multiple databases.After thorough screening, 77 RCTs  were included in this study.The study encompassed a cohort of 43,561 patients diagnosed with HF, consisting of 11,734 patients with HFpEF and 31,827 patients with HFrEF.A detailed description of the literature search and screening process is illustrated in Figure 1, while the baseline characteristics are outlined in Table 1.Among the 77 selected articles, the outcome indicators related to HFpEF or HFrEF were simultaneously reported in 5 articles, 22 focused on HFpEF, and the remaining studies were centered on HFrEF.Specifically, 5 studies investigated canagliflozin treatment, which involved a total of 453 patients; 55 studies examined dapagliflozin treatment, with a collective enrollment of 16,201 patients; 16 studies utilized empagliflozin, which included 21,024 patients; 1 study explored the efficacy of ertugliflozin, which enrolled 478 patients; 1 study evaluated ipragliflozin treatment, with a cohort of 68 patients; and 4 studies analyzed the effects of sotagliflozin, which involved a total of 5,537 patients.Notably, except for empagliflozin and dapagliflozin, no studies directly compared the remaining four types of SGLT2i.

Bias risk evaluation
The results of the bias risk evaluation are presented in Figure 2 and Supplementary Figure S1.For random sequence generation, 77 studies employing a random number table or a random Excel table were identified as low risk; 33 studies provided detailed descriptions of their allocation concealment procedures; however, the remaining studies lacked such descriptions.Regarding implementation bias, 29 studies were defined as high risk, 15 studies did not provide sufficient details, and the rest were classified as low risk.For the assessment of outcome data, one study was identified as high risk due to insufficient details, one was poorly described, and the others were considered low risk.All studies reported complete data for outcomes.Outcome selection bias indicated that 72 studies were classified as low risk, while 5 required further clarification.The results of other preferences showed that seven studies were defined as high risk, two were poorly described, and the remaining studies were assessed as low risk.

CV death and all-cause death
As shown in Table 2, empagliflozin, dapagliflozin, and sotagliflozin showed no difference in reducing all-cause mortality and cardiovascular mortality compared to placebo.The network plot is shown in Figure 3D, while the ranking based on SUCRA values is presented in Table 3.

NT-proBNP
As presented in Table 2,

KCCQ
As detailed in Table 2, compared to placebo, there was no significant difference in the improvement of KCCQ scores in  In bold: values of statistical significance (P < 0.05).

HCT
Table 2 illustrates that empagliflozin [MD = −0.03,CI (−0.04 to −0.02)] significantly increased hematocrit (HCT) in patients with HF compared to placebo.Dapagliflozin did not show any significant difference, and there was no disparity observed among the different SGLT2i treatments.The network plot illustrating these findings is presented in Figure 3O.The ranking based on SUCRA values is as follows: placebo (95%), dapagliflozin (53%), and empagliflozin (1%).

The results of the subgroup analysis The efficacy of SGLT2i in HFrEF patients
The network plot in Figure 4 illustrates that dapagliflozin [RR = 0.44, CI (0.15-1.23)], empagliflozin [RR = 0.75, CI (0.11-5.15)], and sotagliflozin [RR = 0.42, CI (0.05-3.66)] did not significantly reduce the composite of hospitalization for HF and CV death compared to placebo, and there was no difference between the different SGLT2i, as shown in Table 4.The ranking based on SUCRA values is presented in Table 5.Compared with placebo, dapagliflozin significantly improved hospitalization for HF [RR = 0.51, CI (0.33-0.80)] and CV death [RR = 0.73, CI (0.54-0.97)], with no significant differences noted between the different SGLT2i treatments.These findings are outlined in Table 4, and the associated SUCRA rankings are presented in Table 5.Compared to placebo, dapagliflozin reduced all-cause death [RR = 0.69, CI (0.48-0.99)], and dapagliflozin [RR = 0.40, CI (0.18-0.93)] increased a composite of urinary and reproductive infections, with no differences observed between the different SGLT2i treatments.The SUCRA values for these comparisons are also presented in Table 5.

The efficacy of SGLT2i in HFpEF patients
The network plot presented in Figure 5 indicates that compared to placebo, sotagliflozin, dapagliflozin, and empagliflozin did not significantly reduce a composite of hospitalization for HF and CV death, individual hospitalizations for HF and CV death, or all-cause mortality, as detailed in Table 6.No significant differences were observed between the different SGLT2i treatments in these outcomes.The ranking based on SUCRA values is shown in Table 7.
Compared to placebo, dapagliflozin [MD = −272.79,CI (−469.26 to −76.32)] showed significant differences in reducing NT-proBNP levels, while canagliflozin showed no difference.There were no significant differences among the different SGLT2i treatments.The ranking based on SUCRA values is as follows: dapagliflozin (87%), canagliflozin (48%), and placebo (14%).There was no statistical difference in improving LVESV and LVEDV compared to placebo and among the different SGLT2i treatments.The ranking based on SUCRA values is detailed in Table 7.

Consistency and small sample study effect
Comparison-corrected funnel plots were utilized to assess publication bias in the study, focusing on a range of outcome indicators such as a composite of hospitalization for HF and CV death, hospitalization for HF, CV death, all-cause death, urinary and reproductive infections, 6MWT, NT-ProBNP, KCCQ, LAVi, E/e', LVMi, LVEDV, LVESV, LVEF, and HCT.The network funnel plot revealed the presence of small sample effects in the comparison between dapagliflozin and placebo for a composite of hospitalization for HF and CV death (Figure 6A), a composite of urinary and reproductive infections (Figure 6E), CV death (Figure 6C), 6MWT and NT-ProBNP (Figures 6F,G), LVMi (Figure 6K), LVESV (Figure 6M), and LVEDV (Figure 6L).The comparison between canagliflozin and placebo showed a small sample effect in hospitalization for HF (Figure 6B), while the comparison between empagliflozin and placebo indicated small sample effects in CV death (Figure 6C), LVESV (Figure 6M), LVEF (Figure 6N), and allcause death (Figure 6D).

Discussion
This review analyzed 77 RCT involving 43,561 patients using Bayesian network meta-analysis for a comprehensive evaluation.The study encompassed more than 10 outcome indicators, including a composite of hospitalization for HF and CV death, hospitalization for HF and CV death, a composite of urinary and reproductive effects, and an assessment of the cardiac structure.Subgroup analysis was performed based on the ejection fraction of HF.Although the efficacy of SGLT2i varies slightly with different LVEF baselines of patients, it may be beneficial in patients with HF regardless of LVEF baseline.Compared with the placebo, SGLT2i demonstrated a significant advantage in reducing a composite of hospitalization for HF and CV death, hospitalization for HF and CV death, and KCQQ scores while showing no significant impact on reducing all-cause mortality.Indirect comparisons between different SGLT2i suggest improvements in a composite of hospitalization for HF and CV death, hospitalization for HF, and CV death.Sotagliflozin outperformed empagliflozin and dapagliflozin in reducing hospitalization for HF and CV death.However, there is no difference between empagliflozin and dapagliflozin.Nevertheless, given the limited research on sotagliflozin, further investigation is warranted.
Regarding the safety profile in total HF patients, SGLT2i are associated with an increased risk of urinary and reproductive system infections, with dapagliflozin showing the highest risk among them.However, there is no distinction between various types of SGLT2i.A previous meta-analysis (83) showed that, except for dapagliflozin, SGLT2i did not increase incidences of urinary and reproductive system infections, which is consistent with our findings.Moreover, the US Food and Drug Administration has included this potential side effect in its list of adverse reactions.HCT was utilized as a reference indicator to assess low blood volume.The meta-analysis demonstrated that SGLT2i resulted in a rise in HCT relative to placebo, implying an elevated hypotension hazard for SGLT2i.The primary mechanism of action of SGLT2i involves the inhibition of the SGLT2 transporter, predominantly located in the S1 segment of the proximal tubules (84), increasing the excretion of glucose in the urine.Nevertheless, inhibiting SGLT2i also diminishes sodium reabsorption in the proximal tubules, potentially increasing sodium excretion.Previous studies (85,86) reported a correlation between the administration of SGLT2i and a reduction of body weight and blood pressure.
The network meta-analysis results indicated that dapagliflozin and empagliflozin significantly improved NT-proBNP and 6MWT.However, no statistically significant difference was observed among different SGLT2i.While SGLT2i have shown promise in treating HF, it is crucial to determine whether they directly influence the heart's structural function.Therefore, we collected relevant indicators, such as LAVi, E/e', LVMi, and LVEDV, to systematically evaluate the changes in cardiac structure in HF patients treated with SGLT2i.The results showed that SGLT2i significantly reduced LVMi, LVEDV, LAVi, and LVESV and increased LVEF, reflecting significant benefits in improving cardiac systolic and diastolic function.Cardiac anatomy and functional parameters are vital in predicting the prognosis and quality of life in HF patients.Animal studies conducted   According to the grading of HFpEF by the European and American Heart Association, this study conducted subgroup analysis based on ejection fraction.The HFpEF (EF ≥ 50%) group did not show significant differences in reducing a composite of hospitalization for HF and CV death, hospitalization for HF, CV death, and all-cause death.No significant differences were observed between different SGLT2i.However, some meta-analyses have shown that (90-92) SGLT2i can reduce a composite of HF and CV death hospitalizations.However, the previous study defined HFpEF as EF greater than 40%, which differs from our study.Therefore, our study should be more convincing.Regarding the safety of HFpEF patients, SGLT2i also present risks of urinary and reproductive infections, with empagliflozin and sotagliflozin being notable culprits.Canagliflozin has demonstrated higher safety compared to sotagliflozin in this aspect.In terms of improving ventricular remodeling, compared to placebo, SGLT2i have shown improvement in LAVi, E/e', LVEF, and LVMi.However, no significant differences were observed in LVESV and LVEDV, and there was no difference between different SGLT2i.The mechanism of HFpEF remains unclear, and left ventricular diastolic dysfunction is considered the main pathophysiological mechanism underlying the occurrence of HFpEF (93).Our research also confirmed that SGLT2i can improve the diastolic function of HFpEF patients.Typically, remodeling the structure of the patient's heart can significantly enhance their prognosis and quality of life.Unfortunately, there has been limited research on the quality of life scores of HFpEF patients; thus, this outcome measure was not included in our analysis.In the subgroup analysis of HFrEF (EF <50%), the network meta-analysis results revealed significant effects of SGLT2i in reducing hospitalization for HF, CV death, all-cause death, NT-ProBNP, and 6MWT.Interestingly, this finding contrasts with the statistical results obtained before conducting the subgroup analysis, indicating the importance of evaluating the contribution of SGLT2i to HF based on ejection fraction.Furthermore, SGLT2i showed significant advantages in improving all-cause death.The indirect comparison revealed no statistical difference between different SGLT2i.Regarding the safety of HFrEF, dapagliflozin significantly increased the risk of a composite of urinary and reproductive infections compared to placebo.Additionally, our analysis revealed that SGLT2i could enhance KCCQ scores in HFrEF patients.Regarding ventricular remodeling, our study revealed that SGLT2i reduced LVMi, LVESV, and LVEDV and increased LVEF.These findings suggest that SGLT2i can enhance diastolic and systolic function in patients with HFrEF, thereby potentially augmenting the prognostic outcomes for these patients.The therapeutic effect of SGLT2i on cardiac structural remodeling was found to be significantly better in HFrEF patients compared to HFpEF patients, with SGLT2i demonstrating superiority in improving cardiac diastolic function in HFpEF patients.Consistent with our findings, a previous meta-analysis (94) showed that empagliflozin had a more significant effect in improving cardiac structure.
This study presents several limitations.① This study mainly focuses on empagliflozin and dapagliflozin, with relatively little research available on canagliflozin, sotagliflozin, ipragliflozin, and ertugliflozin.Future research should explore these alternative SGLT2i to provide a more comprehensive understanding of their efficacy and safety profiles.② Currently, there is only one direct comparison between dapagliflozin and empagliflozin available in current literature, leading to an indirect evaluation of the efficacy and safety of canagliflozin, sotagliflozin, ipragliflozin, and ertugliflozin in treating HF patients.Consequently, a potential bias exists between the reported results and the actual drug performances, underscoring the need for further directcontrolled trials to validate their efficacy and safety profiles.③ There are variations in baseline characteristics such as gender, age, race, and chronic medical conditions among the included studies, potentially resulting in clinical heterogeneity.④ Variations in follow-up durations between the six SGLT2i drug studies and within individual studies for each drug could introduce bias into the study results.⑤ The limited number of studies on HF with HFpEF (EF ≥ 50%) underscores the necessity for more research to substantiate the relevant findings.

Conclusion
In summary, SGLT2i can significantly improve the prognosis of all patients with HF despite the associated increased risk of urinary and reproductive infections.Overall, HF patients benefit from enhanced cardiac remodeling, with those with HFrEF experiencing the most substantial benefits.Indirect comparisons between different SGLT2i revealed no significant differences in HFrEF.Among the six types of SGLT2i, sotagliflozin demonstrated superiority over empagliflozin and dapagliflozin in reducing hospitalization for HF and cardiovascular death in total HF.Canagliflozin exhibited higher safety than sotagliflozin regarding urinary and reproductive infections in patients with HFpEF.Overall, SGLT2i showed better efficacy in patients with HFrEF than those with HFpEF.

FIGURE 3 A
FIGURE 3 A network plot of each comparison in all eligible trials in HFrEF or HFpEF.(A) The network plot of each comparison in terms of a composite of hospitalization for HF and CV death.(B) The network plot of each comparison in terms of hospitalization for HF.(C) The network plot of each comparison in terms of CV death.(D) The network plot of each comparison in terms of all-cause death.(E) The network plot of each comparison in terms of a composite of urinary and reproductive infections.(F) The network plot of each comparison in terms of 6 min walk distance.(G) The network plot of each comparison in terms of NT-proBNP.(H) The network plot of each comparison in terms of KCCQ.(I) The network plot of each comparison in terms of LAVi.(J) The network plot of each comparison in terms of E/e'.(K) The network plot of each comparison in terms of LVMi.(L) The network plot of each comparison in terms of LVEDV.(M) The network plot of each comparison in terms of LVESV.(N) The network plot of each comparison in terms of LVEF.(O) The network plot of each comparison in terms of HCT.

FIGURE 4 A
FIGURE 4 A network plot of each comparison in all eligible trials in HFrEF.(A) The network plot of each comparison in terms of a composite of hospitalization for HF and CV death.(B) The network plot of each comparison in terms of hospitalization for HF.(C) The network plot of each comparison in terms of CV death.(D) The network plot of each comparison in terms of all-cause death.(E) The network plot of each comparison in terms of a composite of urinary and reproductive infections.(F) The network plot of each comparison in terms of 6 min walk distance.(G) The network plot of each comparison in terms of NT-proBNP.(H) The network plot of each comparison in terms of KCCQ.(I) The network plot of each comparison in terms of LAVi.(J) The network plot of each comparison in terms of E/e'.(K) The network plot of each comparison in terms of LVMi.(L) The network plot of each comparison in terms of LVEDV.(M) The network plot of each comparison in terms of LVESV.(N) The network plot of each comparison in terms of LVEF.

FIGURE 5 A
FIGURE 5 A network plot of each comparison in all eligible trials in HFpEF.(A) The network plot of each comparison in terms of a composite of hospitalization for HF and CV death.(B) The network plot of each comparison in terms of hospitalization for HF.(C) The network plot of each comparison in terms of CV death.(D) The network plot of each comparison in terms of all-cause death.(E) The network plot of each comparison in terms of a composite of urinary and reproductive infections.(F) The network plot of each comparison in terms of NT-proBNP.(G) The network plot of each comparison in terms of E/e' (H) The network plot of each comparison in terms of LVMi.(I) The network plot of each comparison in terms of LVEDV.(J) The network plot of each comparison in terms of LVESV.(K) The network plot of each comparison in terms of LVEF.

TABLE 1
Characteristics of included studies.

TABLE 1 Continued
FIGURE 2Risk of bias summary of all eligible RCTs evaluating the effect of SGLT2i in HFrEF or HFpEF.

TABLE 2
Comparison of the efficacy and safety of different SGLT2i in treating HF [RR and mean difference (95% CI)].

TABLE 3
Ranking probability of the efficacy of drug in patients with HF.

TABLE 4
Comparison of the efficacy and safety of different SGLT2i in treating HFrEF [RR and mean difference (95% CI)].

TABLE 5
Ranking probability of the efficacy of drug in patients with HFrEF.

TABLE 6
Comparison of the efficacy and safety of different SGLT2i in treating HFpEF [RR and mean difference (95% CI)].

TABLE 7
Ranking probability of the efficacy of four in patients with HFpEF.